Methods of treatment of cholestatic diseases

ABSTRACT

The present invention relates to the use of compound 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-carboxydimethyl-methyloxyphenyl]prop-2-en-1-one (Elafibranor or GFT505) for treating cholestatic diseases, and more specifically PBC and/or PSC.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/EP2017/057634, filed Mar. 30, 2017, which claims the benefit ofEuropean Application No. 16305381.2, filed Mar. 31, 2016. The contentsof both applications are hereby incorporated by reference in theirentirety.

TECHNICAL FIELD

The present invention relates to the field of medicine, in particularthe treatment of cholestatic diseases, and more specifically PBC and/orPSC.

BACKGROUND

The present invention is dedicated to cholestasis or cholestaticdiseases, also mainly characterized by two distinct pathologies: PBC(Primary Biliary Cholangitis, previously named Primary Biliary Cirrhosis(Beuers et al, 2015)) and/or PSC (Primary Sclerosing Cholangitis).

Cells in the liver produce bile, which passes through ducts within theliver to the gallbladder. Bile is a digestive liquid that is made in theliver. It travels through the bile ducts to the gallbladder and thesmall intestine, where it helps digest fats and fatty vitamins.

Cholestasis is a condition that results from an impairment of bileformation or bile flow to the gallbladder and duodenum (first section ofthe small intestine). The effects of cholestasis are profound andwidespread, leading to worsening liver disease and systemic illness,liver failure, and the need for liver transplantation.

Cholestasis may be classified as intrahepatic or extrahepatic.Intrahepatic cholestasis primarily involves the bile canaliculi and theintrahepatic bile ducts. Extrahepatic cholestasis involves theextrahepatic ducts, the common hepatic duct or the common bile duct.

Primary Biliary Cholangitis, or PBC, is a chronic inflammatoryintrahepatic, or long-term, liver disorder that slowly destroys thesmall-to-medium-sized bile ducts (tube-like structures that carry bile)within the liver. In patients with PBC, the bile ducts are destroyed byinflammation. This causes bile to remain in the liver, where gradualinjury damages liver cells and causes cirrhosis, or scarring of theliver.

PBC is considered as a rare disease, with a prevalence of 40 cases per100000. The diagnosis of PBC is typically established between the agesof 30 and 60 years. PBC develops in all races, and 90% of cases occur inwomen. The disease accounts for 2 to 3% of deaths due to cirrhosis(Boonstra et al, 2012; Zetterman, 2015).

Primary Biliary Cholangitis (PBC) was previously named Primary BiliaryCirrhosis, but health officials from around the world haveoverwhelmingly supported changing the name of Primary Biliary Cirrhosisto Primary Biliary Cholangitis. Since cirrhosis occurs only in the latestage, the name primary biliary cirrhosis is actually a misnomer forpatients in the earlier stages of the illness. Changing the name toprimary biliary cholangitis will better serve patients and the medicalcommunity worldwide (Beuers et al, 2015).

Although genetic or environmental factors are associated with the riskof PBC, the causes are still unknown, and most experts consider PBC asan autoimmune disease.

PBC advances slowly. Many patients lead active and productive lives formore than 10 to 15 years after diagnosis. Patients who show no symptomsat the time of diagnosis often remain symptom-free for years. Patientswho have normal liver tests on treatment may have a normal lifeexpectancy. PBC is a chronic illness and may lead to life-threateningcomplications, especially after cirrhosis develops.

The first signs being a generalized fatigue (in 70% of cases) and theappearance of pruritus and itching. However, most of the patients areasymptomatic in the early stage of the disease. The diagnosis isestablished by standard biomedical analyses including the measurement ofanti-mitochondrial antibodies (AMAs, which reflect the autoimmunecharacter), and liver enzymes such as alkaline phosphatase.

Ursodeoxycholic acid (UDCA) and Obeticholic acid (OCA) are the onlytherapies approved by the FDA for the treatment of PBC (Purohit &Cappell, 2015). UDCA is the first line therapy for PBC but is efficientin only 60% of patients. The other 40% respond weakly or not at all tothe treatment, and are therefore at high risk of developing cirrhosis,liver insufficiency, and ultimately requiring a liver transplantation.

Primary Sclerosing Cholangitis (PSC) is a chronic, or long-term, diseasethat slowly damages the extra- and intrahepatic bile ducts. In patientswith PBC, the bile ducts are destroyed by inflammation, and in patientswith PSC, they become blocked due to inflammation and deteriorating. Inboth cases, this causes bile to accumulate in the liver, where itgradually damages liver cells and causes cirrhosis, or damage of theliver.

As described for PBC, the cause is still unknown but the immune systemis believed to play a major role. About 70 percent of patients are men.It may be related to bacterial or viral infections, as well as problemsin the immune system. Genetic factors may also play a role. PSC isconsidered an uncommon disease, but recent studies suggest that it maybe more common than previously thought. This disease is often associatedwith inflammatory diseases of the intestine such as hemorrhagicrectocolitis, and accounts for 40% of liver abnormalities related withthis disease.

It is a rare disease that affects predominantly men (70% of thepatients) with an estimated prevalence of 1 to 5 cases per 10 000persons.

PSC advances very slowly. Many patients may have the disease for yearsbefore symptoms develop. Symptoms may remain at a stable level, they maycome and go, or they may progress gradually. Liver failure may occur10-15 years after diagnosis, but this may take even longer for some PSCpatients. Many people with PSC will ultimately need a liver transplant,typically about 10 years after being diagnosed with the disease. PSC mayalso lead to bile duct cancer. Endoscopy and MRI tests may be done tomonitor the disease. Many people with PSC do not get symptoms,especially in the early stages of the disease. When symptoms do occurthe most common are fatigue, pruritus, or itching of the skin, andjaundice, a yellowing of the skin and eyes. These symptoms may come andgo, but they may worsen over time. As the disease continues, the bileducts may become infected, which can lead to episodes of fever, chillsand abdominal pain.

Because many PSC patients have no symptoms, the disease is oftendiscovered through abnormal results on routine liver blood tests. Thediagnosis will be completed based on a combination of biochemical,histological and imaging analyses. Formal diagnosis is usually made bycholangiography, an X-ray test involving injection of dye into the bileducts, or by a MRI.

Although UDCA treatment may be beneficial for some patients, there iscurrently no therapy that significantly reduces the risk of death or theneed for liver transplantation, which still remains the only solutionfor patient survival.

The need for novel therapeutic options for the management of cholestaticdiseases, in particular PSC and/or PBC, is still clear and urgent.

Elafibranor is being developed by Genfit for the treatment ofnon-alcoholic steatohepatitis. The present inventors herein show thatthe profile of Elafibranor also makes it a therapeutic asset for thetreatment of PBC.

SUMMARY OF INVENTION

A clinical study has surprisingly shown that the treatment of patientswith 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-en-1-one (Elafibranor, formely called GFT505)provides a relevant reduction of biochemical markers in the plasma,demonstrating that this compound is advantageous for the treatment ofcholestatic diseases.

The present invention relates to elafibranor for use for the treatmentof a cholestatic disease. The present invention also provides the use ofelafibranor in the preparation of a pharmaceutical composition fortreating a cholestatic disease.

In a further embodiment, the present invention also discloses the use ofelafibranor in the manufacture of a medicament for treating acholestatic disease.

The present invention further relates to a method for treating acholestatic disease in a subject in need thereof, comprisingadministering a therapeutic effective amount of elafibranor, inparticular thereby inducing a reduction in cholestasis.

In a particular embodiment of the invention, elafibranor is administeredat a dose varying between 0.01 mg and 1 g per administration,preferentially from 1 mg to 150 mg per administration, and morepreferably from 70 mg to 130 mg. In a particular embodiment, elafibranoris administered once a day. In another particular embodiment,elafibranor is administered once a day at a dose of 80 or 120 mg

The invention also provides a pharmaceutical composition comprisingcompound elafibranor for use for treating a cholestatic disease.

According to the invention, the pharmaceutical composition may beformulated in the form of injectable suspensions, gels, oils, pills,tablets, suppositories, powders, gel caps, capsules, aerosols or meansof galenic forms or devices assuring a prolonged and/or slow release.

In particular, the pharmaceutical composition comprises compoundelafibranor and a pharmaceutically acceptable carrier and/or excipient.

In another embodiment of the invention, the invention also discloses akit for treating a cholestatic disease or for use for treating acholestatic disease, the kit comprising elafibranor. According to thepresent invention, the disclosed method, compound, uses, composition orkit concern the treatment of a cholestatic disease preferably selectedin the group consisting in Primary Biliary Cholangitis, PrimarySclerosing Cholangitis, Intrahepatic Cholestasis of Pregnancy,Progressive Familial Intrahepatic Cholestasis, Biliary atresia,Cholelithiasis, Infectious Cholangitis, Cholangitis associated withLangerhans cell histiocytosis, Alagille syndrome, Nonsyndromic ductalpaucity, Drug-induced cholestasis, and Total parenteralnutrition—associated cholestasis.

In a preferred embodiment, the cholestatic disease is PBC or PSC.

In another preferred embodiment, the cholestatic disease is PBC.

DESCRIPTION OF THE FIGURES AND TABLES

Abbreviations used in the figures, in the tables, and in the text:

-   -   AE adverse event    -   ALP Alkaline Phosphatase    -   ALT Alanine Transaminase    -   AMA anti-mitochondrial antibody    -   ASBTi apical sodium-codependent bile acid transporter inhibitors    -   AST Aspartate Aminotransferase    -   BCL6 B-cell lymphoma 6    -   C4 serum 7α-hydroxy-4-cholesten-3-one    -   CDCA chenodeoxycholic acid    -   CK-18 cytokeratine-18    -   CPK creatine phosphokinase    -   DCA deoxycholic acid    -   ECG electrocardiogram    -   eGFR estimated glomerular filtration rate    -   FDA Food and Drug Administration    -   FGF19 Fibroblast growth factor 19    -   FXR Farnesoid X receptor    -   γGT gamma-Glutamyl-Transferase    -   HBV hepatitis B virus    -   HCB hepatitis C virus    -   HDL-C High Density Lipoprotein-Cholesterol    -   HIV human immunodeficiency virus    -   IC informed consent    -   ICP Intrahepatic Cholestasis of Pregnancy    -   IgM immunoglobulin M    -   IL-6 interleukin-6    -   IRB institutional review board    -   ITT Intention To Treat    -   IVRS interactive voice response system    -   IWRS interactive web response system    -   LDL-C Low Density Lipoprotein-Cholesterol    -   MELD Model for End Stage Liver Disease    -   MRI Magnetic resonance imaging    -   NASH nonalcoholic steatohepatitis    -   NF-κB nuclear factor kappa B    -   NOX NADPH oxidase    -   OCA obeticholic acid    -   PBC Primary Biliary Chlolangitis    -   PFIC Progressive Familial Intrahepatic Cholestasis    -   PK pharmacokinetics    -   PPAR Peroxisome proliferator-activated receptor    -   PSC Primary Sclerosing Cholangitis    -   QOL quality of life    -   TG TriGlyceride    -   TGF-β transforming growth factor beta    -   TIPS transjugular intrahepatic portosystemic shunts    -   TNF-α tumor necrosis factor alpha    -   TPN Total parenteral nutrition    -   UDCA ursodeoxycholic acid    -   ULN upper limit of normal    -   VAS visual analogue score

FIG. 1. Dosage of Alkaline Phosphatase

NASH patients treated with both elafibranor doses (80 mg and 120 mg)improved alkaline phosphatase levels compared to placebo group. FIG. 1shows changes from baseline in liver enzyme in treatment groups of theefficacy evaluable set (n=237). Results are expressed in mean values ofchanges from baseline during treatment with placebo (n=77), elafibranor80 mg (n=82) and elafibranor 120 mg (n=78). Error bars represent 95%Cls.

FIG. 2: Dosage of γ-GT

NASH patients treated with both elafibranor doses (80 mg and 120 mg)improved γ-GT levels compared to placebo group. FIG. 2 shows changesfrom baseline in liver enzyme in treatment groups of the efficacyevaluable set (n=237). Results are expressed in mean values of changesfrom baseline during treatment with placebo (n=77), elafibranor 80 mg(n=82) and elafibranor 120 mg (n=78). Error bars represent 95% Cls.

FIG. 3: Dosage of C4

FIG. 3a : NASH patients treated with both elafibranor doses (80 mg and120 mg) improved C4 levels compared to placebo group. FIG. 3a showschanges from baseline in treatment groups of the efficacy evaluable set(n=62). Results are expressed in mean values of changes from baselineduring treatment with placebo (n=23), elafibranor 80 mg (n=16) andelafibranor 120 mg (n=23).

FIG. 3b : Patients treated with both elafibranor doses (80 mg and 120mg) improved C4 levels reported to placebo. FIG. 3b shows changes fromplacebo group to treatment groups of the efficacy evaluable set (n=62).Results are expressed in mean values of changes from baseline duringtreatment with placebo (n=23), elafibranor 80 mg (n=16) and elafibranor120 mg (n=23).

DETAILED DESCRIPTION OF THE INVENTION

Cholestasis or cholestatic disease is defined as a decrease in bile flowdue to impaired secretion by hepatocytes (hepato-cellular cholestasis)or to obstruction of bile flow through intra- or extrahepatic bile ducts(obstructive cholestasis). In clinical practice, cholestasis is anycondition in which the flow of bile from the liver is slowed or blocked.

Examples of cholestatic diseases are Primary Biliary Cholangitis (PBC)(formely named Primary Biliary Cirrhosis), Primary SclerosingCholangitis (PSC), Intrahepatic Cholestasis of Pregnancy (ICP),Progressive Familial Intrahepatic Cholestasis (PFIC), Biliary atresia,Cholelithiasis, Infectious Cholangitis, Cholangitis associated withLangerhans cell histiocytosis, Alagille syndrome, Nonsyndromic ductalpaucity, Drug-induced cholestasis, Total parenteral nutrition(TPN)-associated cholestasis.

In a particular embodiment, the subject to be treated has PBC. PBC ischaracterized by changes in many blood biochemical parameters. Patients'sera show the enhanced activity of alkaline phosphatase (ALP),γ-glutamyltransferase (gamma glutamyltranspeptidase, γ-GT),5′-nucleotidase (5′-NT), and leucineaminopeptidase (LAP), the higherlevels of bile acids, cholesterol, phospholipids, copper, γ-globulins,and bilirubin, and the lower level of total protein mainly at theexpense of albumin fractions. In PBC, there is a decline in the levelsof bile acids, cholesterol, and lecithin in the hepatic bile portion andtheir simultaneous rises in hepatocytes and blood (Reshetnyak, 2015).Changes in bile acid precursor C4 (7α-hydroxy-4-cholesten-3-one) (C4)can be assessed to characterize PBC.

In a particular embodiment, the patient has PBC and responds at leastpartly to UDCA. In another embodiment, the patient has PBC and does notrespond adequately to UDCA. In a particular embodiment, elafibranor isadministered, preferably orally, to a patient with PBC and inadequateresponse to UDCA, in particular at a dose of 80 or 120 mg.

The term “an effective amount” or “therapeutic effective amount” refersto an amount of the compound sufficient to produce the desiredtherapeutic result and elafibranor is administered in amounts that aresufficient to display the desired effect. In a particular aspect, thedesired effect is an improvement in alkaline phosphatase and/or γ-GTlevels signing a reduction in cholestasis. Accordingly, the inventionalso relates to elafibranor for use in the improvement of ALP and/orγ-GT levels in a subject in need thereof. In particular, elafibranor isadministered for lowering the activity of ALP and/or γ-GT.

In a particular embodiment, elafibranor is administered to a subjectwith PBC for normalizing ALP, albumin and/or bilirubin level(s).

In a particular embodiment, the subject is with PBC and the treatmentresults in a level of ALP lower than 1.67×ULN (upper limit of normal)and total bilirubin within normal limit. The reference range of totalbilirubin is 0.2-1.2 mg/dL. The reference range of direct bilirubin is0.1-0.4 mg/dL. In a particular variant of this embodiment, elafibranoris administered for decreasing ALP level by at least 15%.

In another embodiment, the subject is with PBC and the treatment resultsin a level of ALP lower than 2×ULN (upper limit of normal) and totalbilirubin within normal limit. In a particular variant of thisembodiment, elafibranor is administered for decreasing ALP level by atleast 40%.

In a particular embodiment, elafibranor is administered to a subjectwith PBC, to improve bile acids level such as CDCA, cholic acid,litocholic acid and DCA levels.

In a further embodiment, elafibranor is administered for improving ParisI, Paris II, Toronto I, Toronto II or UK-PBC risk score.

In another embodiment, elafibranor is administered to a subject with PBCfor:

-   -   improving AST, γGT, 5′-nucleotidase, total bilirubin, conjugated        bilirubin, ALT and albumin levels;    -   improving lipid parameters    -   improving C4 and/or FGF19 levels    -   improving IgM levels; and    -   improving 5D-itch scale, PBC 40 QOL, VAS.

The term “treatment” or “treating” refers to therapy, prevention, orprophylaxis of a cholestatic disease in a subject in need thereof. Thetreatment involves the administration of elafibranor (such as via theadministration of a pharmaceutical composition comprising elafibranor)to a subject (e.g. a patient) having a declared disease to prevent,cure, delay, reverse, or slow down the progression of the disease,improving thereby the condition of patients. A treatment may be alsoadministered to subjects that are either healthy or at risk ofdeveloping a cholestatic disease.

The term “subject” refers to a mammal and more particularly a human. Thesubjects to be treated according to the invention can be appropriatelyselected on the basis of several criteria associated with cholestaticpathological processes such as previous and/or present drug treatments,associated pathologies, genotype, exposure to risk factors, as well asany other relevant biomarker that can be evaluated by means of anysuitable immunological, biochemical, or enzymatic method. The subject tobe treated is with PBC, as characterized as follows:

-   -   the presence of at least 2 of the following 3 diagnostic        factors:        -   (i) history of elevated ALP levels for at least 6 months            prior to Day 0 (randomization visit)        -   (ii) positive Anti-Mitochondrial Antibodies (AMA) titers (>            1/40 on immunofluorescence or M2 positive by enzyme-linked            immunosorbent assay (ELISA) or positive PBC-specific            antinuclear antibodies        -   (iii) liver biopsy consistent with PBC    -   ALP≥1.67× upper limit of normal (ULN)    -   optionally, taking UDCA for at least 12 months (stable dose for        ≥6 months) prior to screening visit.

Elafibranor can have different stable isomeric forms.

Synthesis of elafibranor can for example be carried out as described forcompound 29 in WO2004/005233.

Elafibranor can be formulated as pharmaceutically acceptable salts,being slightly- or non-toxic salts obtained from organic or inorganicbases or acids of elafibranor. These salts can be obtained during thefinal purification step of the compound or by incorporating the saltinto the previously purified compound.

The pharmaceutical compositions comprising elafibranor for the treatmentof cholestatic diseases can comprise one or several excipients orvehicles, acceptable within a pharmaceutical context (e.g. salinesolutions, physiological solutions, isotonic solutions, etc., compatiblewith pharmaceutical usage and well-known by one of ordinary skill in theart). These compositions can comprise one or several agents or vehicleschosen among dispersants, solubilisers, stabilisers, preservatives, etc.Agents or vehicles useful for these formulations (liquid and/orinjectable and/or solid) are particularly methylcellulose,hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80,mannitol, gelatin, lactose, vegetable oils, acacia, liposomes, etc.These compositions can be formulated in the form of injectablesuspensions, gels, oils, pills, suppositories, powders, gel caps,capsules, aerosols, etc., eventually by means of galenic forms ordevices assuring a prolonged and/or slow release. For this kind offormulation, agents such as cellulose, carbonates or starches canadvantageously be used.

Elafibranor may be administered in an efficient amount by using apharmaceutical composition as above-defined.

Elafibranor can be administered in different ways and in different formsthat allow administering said compounds in a therapeutically effectiveamount. Thus, for example, it can be administered in a systematic way,per os, by parenteral route, by inhalation, or by injection, such as forexample intravenously, by intra-muscular route, by subcutaneous route,by transdermal route, by intra-arterial route, etc. Oral administrationis the preferential route of administration for pharmaceuticalcompositions comprising elafibranor for the treatment of a cholestaticdisease.

The frequency and/or dose relative to the administration can be adaptedby one of ordinary skill in the art, in function of the patient, thepathology, the form of administration, etc. Typically, elafibranor canbe administered for the treatment of a cholestatic disease at dosesvarying between 0.01 mg and 1 g per administration, preferentially from1 mg to 150 mg per administration, and more preferably from 70 mg to 130mg. Administration can be performed daily or even several times per day,if necessary. In a particular embodiment, elafibranor is administeredonce a day. In another particular embodiment, elafibranor isadministered once a day at a dose of 80 or 120 mg.

In a particular embodiment, the invention relates to the use ofelafibranor for the treatment of a cholestatic disease, in combinationwith at least one other therapeutically active agent. The other activeagent may in particular be selected from other anti-cholestatic agentssuch as UDCA or OCA. The invention thus also relates to the combinationof elafibranor with UDCA or OCA. The invention also relates to thecombination of elafibranor with an anti-cholestatic agent. Otheranti-cholestatic agents include, without limitation:

-   -   apical sodium-codependent bile acid transporter inhibitors        (ASBTi);    -   bile acids;    -   cathepsin inhibitors;    -   CCR antagonists;    -   CD40 inhibitors;    -   CD80 inhibitors;    -   Dual NOX (NADPH oxidase) 1&4 inhibitors;    -   Farnesoid X receptor (FXR) agonists;    -   Fibroblast Growth Factor (FGF) 19 recombinant;    -   Fractalkine ligand inhibitors;    -   ileal sodium bile acid cotransporter inhibitors;    -   Monoclonal antibodies;    -   PPAR alpha agonists;    -   PPAR gamma agonists;    -   PPAR delta agonists;    -   PPARalpha/gamma agonists;    -   PPARalpha/delta agonists;    -   PPAR gamma/delta agonists; and    -   PPAR alpha/gamma/delta agonists or PPARpan agonists.

Illustrative apical sodium-codependent bile acid transporter inhibitorsinclude, without limitation, A-4250; volixibat; maralixibat formelySHP-625; GSK-2330672; elobixibat and CJ-14199.

Illustrative bile acids include, without limitation, obeticholic acidand ursodiol (UDCA).

Illustrative cathepsin inhibitors include, without limitation, VBY-376;VBY-825; VBY-036; VBY-129; VBY-285; Org-219517; LY3000328; RG-7236 andBF/PC-18.

Illustrative CCR antagonists include, without limitation, cenicriviroc(CCR2/5 antagonist); PG-092; RAP-310; INCB-10820; RAP-103; PF-04634817and CCX-872.

Illustrative CD40 inhibitors include, without limitation, FFp-104;xl-050; DOM-0800; XmAb-5485; KGYY-15; FFP-106; TDI-0028 and ABI-793.

Illustrative CD80 inhibitors include, without limitation, RhuDex;FPT-155; ToleriMab; galiximab; SCH-212394; IGM-001; ASP-2408 andSCH-204698.

Illustrative dual NOX (NADPH oxidase) 1&4 inhibitors include, withoutlimitation, GKT-831 (formerly GKT137831) and GKT-901.

Illustrative Farnesoid X receptor (FXR) agonists include, withoutlimitation, obeticholic acid; GS-9674; LJN-452; EDP-305; AKN-083;INT-767; GNF-5120; LY2562175; INV-33; NTX-023-1; EP-024297; Px-103 andSR-45023.

Illustrative Fibroblast Growth Factor 19 (FGF-19) recombinants include,without limitation, NGM-282.

Illustrative Fractalkine ligand inhibitors include, without limitation,E-6011 and KAN-0440567.

Illustrative ileal sodium bile acid cotransporter inhibitors include,without limitation, A-4250; GSK-2330672; volixibat; CJ-14199 andelobixibat.

Illustrative monoclonal antibodies include, without limitation,bertilimumab; NGM-313; IL-20 targeting mAbs; fresolimumab (antiTGFβ)formely GC1008; timolumab formely BTT-1023; namacizumab; omalizumab;ranibizumab; bevacizumab; lebrikizumab; epratuzumab; felvizumab;matuzumab; monalizumab; reslizumab and inebilizumab.

Illustrative PPAR alpha agonists include, without limitation,fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate,binifibrate, clinofibrate, clofibric acid, nicofibrate, pirifibrate,plafibride, ronifibrate, theofibrate, tocofibrate and SR10171;

Illustrative PPAR gamma agonists include, without limitation,Pioglitazone, deuterated pioglitazone, Rosiglitazone, efatutazone,ATx08-001, OMS-405, CHS-131, THR-0921, SER-150-DN, KDT-501,GED-0507-34-Levo, CLC-3001 and ALL-4.

Illustrative PPAR delta agonists include, without limitation, GW501516(Endurabol or({4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}aceticacid)) or MBX8025 (Seladelpar or{2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsylfanyl]-phenoxy}-aceticacid) or GW0742([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid) or L165041 or HPP-593 or NCP-1046.

Illustrative PPAR alpha/gamma agonists (also named glitazars) include,without limitation, Saroglitazar, Aleglitazar, Muraglitazar,Tesaglitazar and DSP-8658.

In addition to elafibranor, illustrative PPAR alpha/delta agonistsinclude, without limitation, T913659.

Illustrative PPAR gamma/delta agonists include, without limitation,linoleic acid (CLA) and T3D-959.

Illustrative PPAR alpha/gamma/delta agonists (or “PPARpan agonists”)include, without limitation, IVA337, TTA (tetradecylthioacetic acid),Bavachinin, GW4148, GW9135, Bezafibrat, Lobeglitazone, and CS038.

In a further embodiment, the present invention provides methods oftreating a cholestatic disease comprising the administration ofelafibranor or the combination of the invention, in particular in theform of a pharmaceutical composition containing this compound.

In another embodiment, the present invention also provides a kit fortreating a cholestatic disease comprising elafibranor, optionally incombination to another anti-cholestatic agent as described above.

The invention is further described with reference to the following,non-limiting, examples.

EXAMPLES Example 1: ALP and γGT Dosages

Adult subjects with non-alcoholic steatohepatitis (age 18-75 years) weretreated at the dose of 80 mg and 120 mg per day of elafibranor over 52weeks.

A total of 276 NASH patients were randomized: 92 in the placebo group,93 in the elafibranor 80 mg group and 91 in the elafibranor 120 mggroup. Two patients did not receive the study medication and theremaining 274 patients constitute the ITT (intention to treat)population. 33 patients (12%) dropped out during the study. Final liverbiopsies were available in 237 patients (77, 82, and 78 patients in theplacebo, elafibranor 80 mg, and elafibranor 120 mg groups respectively).

Patients were followed every 2 months with clinical and laboratoryevaluations.

Patients treated with both elafibranor doses (80 mg and 120 mg) improvedliver function tests (ALT, γGT and alkaline phosphatase) and lipidparameters (triglycerides, LDLcholesterol, HDL-cholesterol).

Elafibranor lowered alkaline phosphatase (see FIG. 1) and γ-glutamyltranspeptidase (see FIG. 2) in a dose-dependent manner, showing theinterest of elafibranor for the treatment of cholestatic diseases.

Beneficial effects of elafibranor on liver function were consistentlyobserved in all patients treated for 1 to 3 months with 80 mg/dayelafibranor. Significant reductions in circulating levels of γGT and ALPwere observed and reached up to −29% for γGT and −25% for ALP inelafibranor treated groups compared to placebo. In addition, ininsulin-resistant patients, elafibranor treatment induced a significantreduction in ALT (−20% compared to placebo), while the level ofaspartate aminotransferase (AST) was unchanged.

In the Phase 2a and 2b program, elafibranor has consistently shown asignificant decrease in liver enzymes, notably in ALP. A decrease in ALPlevels is recognized as a particularly relevant surrogate marker for thetreatment of PBC, and was recently used as the basis for FDA approval ofOCA in this indication.

The subjects show a dose-related improvement in their disease as shownby a decrease in ALP and γGT.

Example 2: C4 Dosage

The effect of elafibranor was further tested in relation to parametersmore directly related to cholestatic diseases than ALP and γGT levels.Thus, it was explored whether treated subjects show a decrease in plasmatotal bile acids. The measurement of serum 7α-hydroxy-4-cholesten-3-one(7α-HCO, or 7αC4, or C4) is a method for monitoring the enzymaticactivity of hepatic cholesterol 7α-hydroxylase, the rate-limiting andmajor regulatory enzyme in the synthesis of bile acids. Thus a decreasein C4 level reflects a decrease in total bile acids in the patient.

In NASH patients with high ALP level at baseline, elafibranor was orallyadministered at a dose of either 80 mg or 120 mg per day over 52 weeks.

A total of 62 NASH patients with high ALP levels were randomized: 23 inthe placebo group, 16 in the elafibranor 80 mg group and 23 in theelafibranor 120 mg group.

Bile acids precursor levels were improved in the patients havingreceived both elafibranor doses, in a dose-dependent manner.

Example 3: Clinical Trial for PBC

A multicenter, double-blind, randomized, placebo-controlled, phase 2study clinical trial is conducted in patients with Primary BiliaryCholangitis and inadequate response to ursodeoxycholic acid to evaluatethe efficacy and safety of treatment with elafibranor given orally (80mg daily and 120 mg daily) for 12 weeks.

Primary Objectives

The primary objective is to compare the effect of daily oraladministration of elafibranor 80 mg and 120 mg on changes in serumalkaline phosphatase (ALP) to that of placebo in patients with PBC andinadequate response to ursodeoxycholic acid (UDCA).

Secondary Objectives

The secondary objectives are:

-   -   to assess the response to treatment based on composite        endpoints:        -   ALP<1.67×upper limit of normal (ULN) and total bilirubin            within normal limit and >15% decrease in ALP        -   ALP<2×ULN and total bilirubin within normal limit and >40%            decrease in ALP    -   to assess response according to:        -   Paris I, Paris II, Toronto I, Toronto II, UK-PBC risk score    -   to assess response based on the percent of patients who        normalized ALP    -   to assess response based on the percent of patients who        normalized albumin    -   to assess response based on the percent of patients who        normalized bilirubin    -   to assess the change from baseline in AST, γGT, 5′-nucleotidase,        total bilirubin, conjugated bilirubin, ALT, albumin    -   to assess the change from baseline in lipid parameters    -   to assess the change from baseline in bile acids: CDCA, cholic        acid, litocholic acid, DCA    -   to assess the change from baseline in C4, FGF19    -   to assess the change from baseline in IgM    -   to assess the change from baseline in:        -   5D-itch scale        -   PBC 40 QOL        -   VAS    -   to assess the tolerability and safety of elafibranor in patients        with PBC    -   to assess pharmacokinetics (PK) of elafibranor 80 mg and 120 mg        and its main metabolite in PBC patients and to explore an        exposure-response relationship.

Inclusion Criteria

-   -   1. Must have provided written informed consent (IC)    -   2. Males or females 18 to 75 years of age    -   3. Definite or probable PBC diagnosis as demonstrated by the        presence of at least 2 of the following 3 diagnostic factors:        -   History of elevated ALP levels for at least 6 months prior            to Day 0 (randomization visit)        -   Positive Anti-Mitochondrial Antibodies (AMA) titers (> 1/40            on immunofluorescence or M2 positive by enzyme-linked            immunosorbent assay (ELISA) or positive PBC-specific            antinuclear antibodies        -   Liver biopsy consistent with PBC    -   4. ALP≥1.67× upper limit of normal (ULN)    -   5. Taking UDCA for at least 12 months (stable dose for ≥6        months) prior to screening visit    -   6. Contraception: Females participating in this study must be of        non-childbearing potential or must be using highly efficient        contraception for the full duration of the study and for 1 month        after the end of treatment, as described below:        -   a) Cessation of menses for at least 12 months due to ovarian            failure        -   b) Surgical sterilization such as bilateral oophorectomy,            hysterectomy, or medically documented ovarian failure        -   c) If requested by local IRB regulations and/or National            laws, sexual abstinence may be considered adequate (the            reliability of sexual abstinence needs to be evaluated in            relation to the duration of the clinical trial and the            preferred and usual lifestyle of the subject)        -   d) Using a highly effective non-hormonal method of            contraception (bilateral tubal occlusion, vasectomised            partner or intra-uterine device)        -   e) Double contraception with barrier and highly effective            hormonal method of contraception (oral, intravaginal or            transdermal combined estrogen and progestogen hormonal            contraception associated with inhibition of ovulation, oral,            injectable or implantable progestogen-only hormonal            contraception associated with inhibition of ovulation or            intrauterine hormone-releasing system). The hormonal            contraception must be started at least one month prior to            randomization.

7. Must agree to comply with the trial protocol.

Exclusion Criteria:

-   -   1. History or presence of other concomitant liver diseases        including:        -   Hepatitis B or C virus (HCV, HBV) infection        -   Alcoholic liver disease        -   Definite autoimmune liver disease or overlap hepatitis        -   Gilbert's Syndrome (due to interpretability of bilirubin            levels)        -   Known history of alpha-1 antitrypsin deficiency    -   2. Significant renal disease, including nephritic syndrome,        chronic kidney disease (defined as patients with markers of        kidney damage or estimated glomerular filtration rate [eGFR] of        less than 60 mL/min/1.73 m2).    -   3. Patients with moderate or severe hepatic impairment (defined        as Child-Pugh B/C)    -   4. Platelet count <150×10 3/microliter    -   5. Albumin <3.5 g/dL    -   6. Presence of clinical complications of PBC or clinically        significant hepatic decompensation, including:        -   History of liver transplantation, current placement on a            liver transplant list, or current Model for End Stage Liver            Disease (MELD) score ≥15        -   Patients with cirrhosis/portal hypertension and            complications (or signs and symptoms of cirrhosis/portal            hypertension), including known esophageal varices, poorly            controlled or diuretic resistant ascites, history of            variceal bleeds or related interventions (e.g., insertion of            variceal bands or transjugular intrahepatic portosystemic            shunts [TIPS]), and hepatic encephalopathy, history or            presence of spontaneous bacterial peritonitis,            hepatocellular carcinoma        -   Hepatorenal syndrome (type I or II) or screening serum            creatinine >2 mg/dL (178 μmol/L)    -   7. Administration of the following medications is prohibited as        specified below:        -   2 months preceding screening and throughout the trial (up to            the last study visit): fibrates or obeticholic acid,            glitazones        -   3 months prior to screening and throughout the trial (up to            the last study visit)): azathioprine, colchicine,            cyclosporine, methotrexate, mycophenolate mofetil,            pentoxifylline; budesonide and other systemic            corticosteroids; and potentially hepatotoxic drugs            (including α-methyl-dopa, sodium valproic acid, isoniazide,            or nitrofurantoin)        -   12 months prior to inclusion visit and throughout the trial            (up to the last study visit): antibodies or immunotherapy            directed against interleukins or other cytokines or            chemokines    -   8. If female: known pregnancy, or has a positive urine pregnancy        test (confirmed by a positive serum pregnancy test), or        lactating    -   9. Known history of human immunodeficiency virus (HIV) infection    -   10. Known hypersensitivity to the investigational product or any        of its formulation excipients

Randomization

Patients who satisfy all eligibility criteria will be randomized in a1:1:1 ratio to one of the following groups:

-   -   Elafibranor 80 mg    -   Elafibranor 120 mg    -   Placebo

A central randomization system will be used (interactive voice/webresponse system [IVRS/IWRS]).

Primary Endpoint

The primary endpoint is the relative change in serum ALP from baselineto end of treatment in each elafibranor arm, compared to placebo

Secondary Endpoint

-   -   Response rate in elafibranor 80 mg and 120 mg and placebo groups        with response defined as ALP less than 1.67 times ULN and total        bilirubin within normal limits and ALP reduction >15%.    -   Response rate in elafibranor 80 mg and 120 mg and placebo groups        with response defined as ALP less than 2 times ULN and total        bilirubin within normal limits and ALP reduction >40%    -   Response rate according to Paris I, Paris II, Toronto I, Toronto        II, UK PBC risk score    -   Alkaline phosphatase response rates of 10%, 20% and 40% decrease    -   Response rate in elafibranor 80 mg and 120 mg and placebo groups        with response defined as percent of patients with normalized ALP        at the end of treatment    -   Response rate in elafibranor 80 mg and 120 mg and placebo groups        with response defined as percent of patients with normalized        bilirubin at the end of treatment    -   Response rate in elafibranor 80 mg and 120 mg and placebo groups        with response defined as percent of patients with normalized        albumin at the end of treatment    -   Changes from baseline in:        -   Gamma-glutamyl transferase (γGT)        -   Alanine aminotransferase (ALT)        -   Aspartate aminotransferase (AST)        -   5′-nucleotidase        -   Bilirubin (total and conjugated)        -   Albumin        -   total cholesterol, LDL-chol, HDL-Chol, Triglycerides        -   Bile acids: CDCA, cholic acid, litocholic acid, DCA        -   C4, FGF19        -   IgM        -   Quality of Life: PBC 40 QOL        -   Pruritus: 5-D Pruritus Questionnaire and Visual Analogue            Score (VAS)        -   Biomarkers of inflammation and liver fibrosis: TNF-α, TGF-β,            IL-6, CK-18 and lysophosphatidic acid    -   Plasma concentrations of elafibranor and its main metabolite and        exposure-response relationship    -   Adverse Events (AEs)    -   Cardiovascular parameters (12-lead ECG, heart rate, blood        pressure)    -   Hematology and safety parameters

It is expected that elafibranor induces a significant reduction in serumALP from baseline to end of treatment, compared to placebo. In addition,it is expected that elafibranor induces significant improvement in atleast one of the secondary endpoints.

REFERENCES

-   Ali A, Byrne T, Lindor K (2015) Orphan drugs in development for    primary biliary cirrhosis: challenges and progress. Orphan Drugs:    Research and Reviews 2015: 83-97-   Beuers U, Gershwin M E, Gish R G, Invernizzi P, Jones D E., Lindor    K, Ma X, Mackay I R, Pares A, Tanaka A, Vierling J M, Poupon    R (2015) Changing nomenclature for PBC: from ‘cirrhosis’ to    ‘cholangitis’. Gut 64: 1671-1672-   Boonstra K, Beuers U, Ponsioen C Y (2012) Epidemiology of primary    sclerosing cholangitis and primary biliary cirrhosis: a systematic    review. J Hepatol 56: 1181-1188-   Ghonem N S, Assis D N, Boyer J L (2015) Fibrates and cholestasis.    Hepatology 62: 635-643-   Lens S, Leoz M, Nazal L, Bruguera M, Pares A (2014) Bezafibrate    normalizes alkaline phosphatase in primary biliary cirrhosis    patients with incomplete response to ursodeoxycholic acid. Liver Int    34: 197-203-   Purohit T, Cappell M S (2015) Primary biliary cirrhosis:    Pathophysiology, clinical presentation and therapy. World J Hepatol    7: 926-941-   Boursier J, Abdelmalek M, Caldwell S, Drenth J, Anstee Q M, Hum D,    Hanf R, Roudot A, Megnien S, Staels B, Sanyal A (2016) Elafibranor,    an Agonist of the Peroxisome Proliferator-Activated Receptor-alpha    and -delta, Induces Resolution of Nonalcoholic Steatohepatitis    Without Fibrosis Worsening. Gastroenterology 150: 1147-1159 el 145-   Reshetnyak V I (2015) Primary biliary cirrhosis: Clinical and    laboratory criteria for its diagnosis. World J Gastroenterol 21:    7683-7708-   Zetterman R (2015) Finding the Patient With Primary Biliary    Cirrhosis. Medscape, News & Perspective available online on 14 Mar.    2016

The invention claimed is:
 1. A method for treating primary biliarycholangitis (PBC), the method comprising administering to a subjecthaving PBC and inadequate response to ursodeoxycholic acid atherapeutically effective amount of a composition comprisingelafibranor.
 2. The method according to claim 1, wherein saidcomposition is formulated in a form selected from the group consistingof an injectable suspension, a gel, an oil, a pill, a suppository, apowder, a gel cap, a capsule, an aerosol, and a galenic form or deviceassuring a prolonged and/or slow release.
 3. The method according toclaim 1, wherein elafibranor is administered orally once daily at a doseof 80 or 120 mg/day.
 4. The method according to claim 1, whereinelafibranor is administered at a dose of 70 mg to 130 mg peradministration.
 5. The method according to claim 1, wherein elafibranoris administered at a dose of 80 mg per administration.
 6. The methodaccording to claim 5, wherein elafibranor is administered orally.
 7. Themethod according to claim 1, wherein elafibranor is administered at adose of 120 mg per administration.
 8. The method according to claim 7,wherein elafibranor is administered orally.
 9. The method according toclaim 1, wherein elafibranor is administered orally once daily at a doseof 80 mg.
 10. The method according to claim 1, wherein elafibranor isadministered orally once daily at a dose of 120 mg.